Clinical Pharmacology of Tafenoquine for the radical cure of vivax malaria
James Watson
2022-08-08
TODO:
- Run with updated PK output
- Paper: check effect in volunteers
- Analysis just with DETECTIVE part 1 (randomised allocation)
- Boxplot of half lives across regions
- Association with weight (just in placebo arms)
Preambule
Load data
##
## DETECTIVE_Ph2 DETECTIVE_Ph3 GATHER
## 329 522 251## TQ doses in efficacy analyses:##
## No Radical Cure PQ15 TQ100 TQ300 TQ50
## 186 265 56 482 55
## TQ600
## 56## [1] 482## [1] 7.692307## [1] 4.929577## 27 patients were lost to follow-up before 1 month## 39 patients were lost to follow-up before 4 months## 125 patients were lost to follow-up before 6 months##
## No Radical Cure PQ15 TQ100 TQ300 TQ50
## 182 257 56 469 54
## TQ600
## 55## A total of 634 patients received TQ in the efficacy population with doses varying from 0.5 to 14.3 mg/kg##
## 0 1
## 775 298##
## 0 1
## 713 360## Warning: NAs introduced by coercionData summaries
Table 1
## tqcat tqmgkgtot
## 1 No radical cure 0.000000
## 2 PQ 0.000000
## 3 [0.01,3.75) 1.987331
## 4 [3.75,6.25) 4.893435
## 5 [6.25,8.75) 6.936322
## 6 [8.75,15] 10.696189## tqcat mean n total
## 1 No radical cure 55.5 101 182
## 2 PQ 22.2 57 257
## 3 [0.01,3.75) 33.7 57 169
## 4 [3.75,6.25) 21.5 79 368
## 5 [6.25,8.75) 7.4 4 54
## 6 [8.75,15] 0.0 0 43## mean age:## tqcat age
## 1 No radical cure 35
## 2 PQ 36
## 3 [0.01,3.75) 37
## 4 [3.75,6.25) 36
## 5 [6.25,8.75) 36
## 6 [8.75,15] 33## SD age:## tqcat age
## 1 No radical cure 14.1
## 2 PQ 14.4
## 3 [0.01,3.75) 13.4
## 4 [3.75,6.25) 14.2
## 5 [6.25,8.75) 17.2
## 6 [8.75,15] 14.4## tqcat sex
## 1 No radical cure 50
## 2 PQ 77
## 3 [0.01,3.75) 43
## 4 [3.75,6.25) 95
## 5 [6.25,8.75) 24
## 6 [8.75,15] 9## tqcat sex
## 1 No radical cure 27
## 2 PQ 30
## 3 [0.01,3.75) 25
## 4 [3.75,6.25) 26
## 5 [6.25,8.75) 44
## 6 [8.75,15] 21## tqcat weight
## 1 No radical cure 62
## 2 PQ 63
## 3 [0.01,3.75) 72
## 4 [3.75,6.25) 63
## 5 [6.25,8.75) 51
## 6 [8.75,15] 57## tqcat weight
## 1 No radical cure 12.0
## 2 PQ 12.1
## 3 [0.01,3.75) 20.1
## 4 [3.75,6.25) 8.7
## 5 [6.25,8.75) 13.3
## 6 [8.75,15] 7.3##
## No radical cure PQ [0.01,3.75) [3.75,6.25) [6.25,8.75) [8.75,15]
## Brazil 55 80 61 105 6 3
## Cambodia 10 8 0 16 2 0
## Colombia 0 5 0 11 0 0
## Ethiopia 14 13 0 18 7 0
## India 9 5 21 8 4 7
## Peru 62 91 56 136 21 18
## Philippines 1 2 0 3 0 0
## Thailand 31 38 31 46 10 15
## Vietnam 0 15 0 25 4 0##
## No radical cure PQ [0.01,3.75) [3.75,6.25) [6.25,8.75) [8.75,15]
## Brazil 30 31 36 29 11 7
## Cambodia 5 3 0 4 4 0
## Colombia 0 2 0 3 0 0
## Ethiopia 8 5 0 5 13 0
## India 5 2 12 2 7 16
## Peru 34 35 33 37 39 42
## Philippines 1 1 0 1 0 0
## Thailand 17 15 18 12 19 35
## Vietnam 0 6 0 7 7 0## tqcat logpara0.0% logpara0.25% logpara0.50% logpara0.75%
## 1 No radical cure 30 2173 5470 11856
## 2 PQ 104 1712 4697 10430
## 3 [0.01,3.75) 129 1447 4320 9456
## 4 [3.75,6.25) 102 1431 4174 10101
## 5 [6.25,8.75) 151 1961 5507 12111
## 6 [8.75,15] 200 1692 6143 13313
## logpara0.100%
## 1 66010
## 2 87380
## 3 51175
## 4 99604
## 5 80535
## 6 56100## tqcat hbday0.1 hbday0.2
## 1 No radical cure 12.9 1.5
## 2 PQ 13.0 1.6
## 3 [0.01,3.75) 12.9 1.8
## 4 [3.75,6.25) 13.2 1.6
## 5 [6.25,8.75) 12.3 1.8
## 6 [8.75,15] 12.6 1.8PK data plot
For supplementary materials
## Rows: 5248 Columns: 18## ── Column specification ────────────────────────────────────────────────────────
## Delimiter: ","
## chr (11): #ID, TIME, AMT, ODV, LNDV, AGE, SEX, BW, ACT, COUNTRY, PID
## dbl (7): MDV, BLQ, CMT, EVID, TYPE, VOMIT, STUDY##
## ℹ Use `spec()` to retrieve the full column specification for this data.
## ℹ Specify the column types or set `show_col_types = FALSE` to quiet this message.## there are a total of 4389 concentrations above LOQ in 718 patients
Kaplan Meier time to recurrence
## [1] 182 257 169 368 54 43
##
## No radical cure PQ [0.01,3.75) [3.75,6.25) [6.25,8.75) [8.75,15]
## Brazil 55 80 61 105 6 3
## Cambodia 10 8 0 16 2 0
## Colombia 0 5 0 11 0 0
## Ethiopia 14 13 0 18 7 0
## India 9 5 21 8 4 7
## Peru 62 91 56 136 21 18
## Philippines 1 2 0 3 0 0
## Thailand 31 38 31 46 10 15
## Vietnam 0 15 0 25 4 0## Range of mg/kg weights:## [1] 0.55 14.29## Median number of methb measurements is 12 (range 2 to 19)##
## 0 1
## 775 298##
## 0 1
## No radical cure 81 101
## PQ 200 57
## [0.01,3.75) 112 57
## [3.75,6.25) 289 79
## [6.25,8.75) 50 4
## [8.75,15] 43 0## Dose (mg) Rec 4 mths (%) n
## 1 No radical cure 55.5 182.0
## 2 PQ 22.2 257.0
## 3 [0.01,3.75) 33.7 169.0
## 4 [3.75,6.25) 21.5 368.0
## 5 [6.25,8.75) 7.4 54.0
## 6 [8.75,15] 0.0 43.0CYP2D6
##
## FALSE TRUE
## 716 384##
## 0 0.5 1 1.5 2
## *1/*1 0 0 0 0 407
## *1/*10 0 0 0 56 0
## *1/*17 0 0 0 34 0
## *1/*3 0 0 3 0 0
## *1/*4 0 0 62 0 0
## *1/*41 0 0 0 27 0
## *1/*5 0 0 24 0 0
## *1/*6 0 0 2 0 0
## *1/*9 0 0 0 10 0
## *10/*10 0 0 35 0 0
## *10/*17 0 0 1 0 0
## *10/*41 0 0 8 0 0
## *17/*17 0 0 3 0 0
## *17/*41 0 0 3 0 0
## *3/*4 3 0 0 0 0
## *3/*9 0 1 0 0 0
## *4/*10 0 1 0 0 0
## *4/*17 0 2 0 0 0
## *4/*4 2 0 0 0 0
## *4/*41 0 7 0 0 0
## *4/*5 3 0 0 0 0
## *4/*9 0 1 0 0 0
## *41/*41 0 0 3 0 0
## *5/*10 0 14 0 0 0
## *5/*41 0 1 0 0 0
## *5/*5 1 0 0 0 0
## *5/*9 0 1 0 0 0
## *9/*41 0 0 1 0 0## CYP2D6 allele frequencies:##
## *1 *10 *17 *3 *4 *41 *5 *6 *9
## 72.1 10.5 3.2 0.5 5.8 3.7 3.1 0.1 1.0##
## 0 0.5 1 1.5 2
## 0 6 0 0 0 0
## 0.25 0 15 0 0 0
## 0.5 3 12 35 0 0
## 0.75 0 0 9 0 0
## 1 0 1 96 0 0
## 1.25 0 0 0 56 0
## 1.5 0 0 5 71 0
## 2 0 0 0 0 407## Activity Score
## CYP2D6 Genotype 0 0.25 0.5 0.75 1 1.25 1.5 2
## *1/*1 0 0 0 0 0 0 0 407
## *1/*10 0 0 0 0 0 56 0 0
## *1/*17 0 0 0 0 0 0 34 0
## *1/*3 0 0 0 0 0 0 3 0
## *1/*4 0 0 0 0 62 0 0 0
## *1/*41 0 0 0 0 0 0 27 0
## *1/*5 0 0 0 0 24 0 0 0
## *1/*6 0 0 0 0 0 0 2 0
## *1/*9 0 0 0 0 0 0 10 0
## *10/*10 0 0 35 0 0 0 0 0
## *10/*17 0 0 0 1 0 0 0 0
## *10/*41 0 0 0 8 0 0 0 0
## *17/*17 0 0 0 0 3 0 0 0
## *17/*41 0 0 0 0 3 0 0 0
## *3/*4 0 0 3 0 0 0 0 0
## *3/*9 0 0 0 0 1 0 0 0
## *4/*10 0 1 0 0 0 0 0 0
## *4/*17 0 0 2 0 0 0 0 0
## *4/*4 2 0 0 0 0 0 0 0
## *4/*41 0 0 7 0 0 0 0 0
## *4/*5 3 0 0 0 0 0 0 0
## *4/*9 0 0 1 0 0 0 0 0
## *41/*41 0 0 0 0 3 0 0 0
## *5/*10 0 14 0 0 0 0 0 0
## *5/*41 0 0 1 0 0 0 0 0
## *5/*5 1 0 0 0 0 0 0 0
## *5/*9 0 0 1 0 0 0 0 0
## *9/*41 0 0 0 0 1 0 0 0Basic data plots
weight
## country outcome_primary.1 outcome_primary.2
## 1 Brazil 26 156
## 2 Cambodia 50 18
## 3 Colombia 36 11
## 4 Ethiopia 16 25
## 5 India 0 9
## 6 Peru 20 162
## 7 Philippines 0 3
## 8 Thailand 11 56
## 9 Vietnam 7 29## country outcome_primary.1 outcome_primary.2
## 1 Brazil 35 310
## 2 Cambodia 53 36
## 3 Colombia 25 16
## 4 Ethiopia 25 52
## 5 India 4 54
## 6 Peru 30 384
## 7 Philippines 17 6
## 8 Thailand 19 171
## 9 Vietnam 9 44
## country weight
## 1 Ethiopia 53
## 2 Philippines 53
## 3 Thailand 54
## 4 Cambodia 55
## 5 Vietnam 57
## 6 India 60
## 7 Peru 62
## 8 Colombia 67
## 9 Brazil 70Methb data
## There are a total of 9632 mthb measurements in 818 patients## Between day 0 and day 20 there are 5816 measurements. Median (range) per patient is 7 (1 to 12)
##
## Call:
## lm(formula = log10(day7_mthb) ~ tqmgkgtot, data = pk_summaries)
##
## Residuals:
## Min 1Q Median 3Q Max
## -1.11911 -0.16721 0.00514 0.18448 0.62429
##
## Coefficients:
## Estimate Std. Error t value Pr(>|t|)
## (Intercept) -0.100671 0.024584 -4.095 4.76e-05 ***
## tqmgkgtot 0.065552 0.004891 13.404 < 2e-16 ***
## ---
## Signif. codes: 0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
##
## Residual standard error: 0.2632 on 648 degrees of freedom
## (72 observations deleted due to missingness)
## Multiple R-squared: 0.2171, Adjusted R-squared: 0.2159
## F-statistic: 179.7 on 1 and 648 DF, p-value: < 2.2e-16
## [1] 18.17566##
## Call:
## lm(formula = t_12_terminal_rescaled ~ AS_score <= 0.5, data = outcome_dat)
##
## Residuals:
## Min 1Q Median 3Q Max
## -11.9579 -2.2104 -0.4231 2.0385 20.6090
##
## Coefficients:
## Estimate Std. Error t value Pr(>|t|)
## (Intercept) 18.8308 0.1894 99.441 <2e-16 ***
## AS_score <= 0.5TRUE -0.8654 0.6329 -1.367 0.172
## ---
## Signif. codes: 0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
##
## Residual standard error: 3.573 on 389 degrees of freedom
## (709 observations deleted due to missingness)
## Multiple R-squared: 0.004783, Adjusted R-squared: 0.002225
## F-statistic: 1.87 on 1 and 389 DF, p-value: 0.1723
Weight based models of tafenoquine efficacy
Logistic regression
## Using all data (n=1073), the odds ratio for recurrence at 4 months for each additional mg/kg of tafenoquine is 0.7 (95% CI 0.65 to 0.75)## Using all data (n=1073), the odds ratio for recurrence at 4 months for each additional mg/kg of primaquine is 0.63 (95% CI 0.55 to 0.71)## Using only patients who got a 300 mg dose (n=469), the odds ratio for recurrence at 4 months for each additional mg/kg of tafenoquine is 0.66 (95% CI 0.51 to 0.86)## Using all patients (n=1073), the odds ratio for recurrence at 6 months for each additional mg/kg of tafenoquine is 0.72 (95% CI 0.67 to 0.77)## Using all patients (n=1073), the odds ratio for recurrence at 6 months for each additional mg/kg of primaquine is 0.61 (95% CI 0.54 to 0.69)EMAX model
load fits
Compare EMAX model fits
Figure 2 in paper: the main mg/kg driving efficacy plot under the EMAX model
## [1] 0.2840664## [1] 0.2067025## [1] 0.1415006## The model estimates that a 15 mg/kg TQ dose reduces 98.64% of all recurrences at 4 months## The E90 is 7.5 mg/kg## The E50 is 3.6 mg/kg
## The E95 is 9 mg/kg## The E90 is 8.4 mg/kg## The E50 is 3.6 mg/kg
## The E95 is 10.3 mg/kgdose-response
## [1] "mean efficacies:"## [1] 68.0794## [1] 87.81331compare logistic and EMAX
## (Intercept) pqmgkgtot tqmgkgtot logpara0
## -1.3718004 -0.4664881 -0.3510041 0.3632042
Number needed to treat
weight versus efficacy
overall number needed to treat
## Mean recurrence for 300 mg:## 2.5% 50% 97.5%
## 10.1 15.1 21.5## Mean recurrence for 450 mg:## 2.5% 50% 97.5%
## 3.5 6.5 11.5## Mean recurrence for 600 mg:## 2.5% 50% 97.5%
## 1.0 3.0 7.7
## NNT (95%CI):## 2.5% 50% 97.5%
## 7.2 11.8 22.0Compare for different parts of the world
##
## Africa Americas Asia-Pacific
## 55 724 321## In Americas the odds ratio for recurrence for each additional mg/kg increase in tafenoquine dose is 0.813 (n=710)
## In Asia-Pacific the odds ratio for recurrence for each additional mg/kg increase in tafenoquine dose is 0.82 (n=311)
## In Africa the odds ratio for recurrence for each additional mg/kg increase in tafenoquine dose is 0.805 (n=52)Compare all ORs for logistic regression models
AUC
## Using all data (n=634), the odds ratio for recurrence at 6 months for each additional mg/kg of tafenoquine is 0.58 (95% CI 0.44 to 0.75)## Using all data (n=634), and adjusted for TQ mg/kg dose, the odds ratio for recurrence at 6 months for each SD in TQ AUC 0.93 (95% CI 0.67 to 1.26)## Using patients who got 300 mg (n=469), the odds ratio for recurrence at 6 months for each additional mg/kg of tafenoquine is 0.85 (95% CI 0.66 to 1.09)CMAX
## Using all data (n=634), the odds ratio for recurrence at 6 months for each 2-fold increase in tafenoquine CMAX is 0.55 (95% CI 0.43 to 0.7)## Using all data (n=634), and adjusted for TQ mg/kg dose, the odds ratio for recurrence at 6 months for a 2-fold increase in TQ Cmax 0.97 (95% CI 0.66 to 1.4)
## Using who got 300 mg (n=469), the odds ratio for recurrence at 6 months for each 10 fold increase in tafenoquine CMAX is 0.43 (95% CI 0.24 to 0.71)Terminal elimination half-life
##
## Call:
## lm(formula = t_12_terminal_rescaled ~ log(weight) + country,
## data = outcome_dat)
##
## Residuals:
## Min 1Q Median 3Q Max
## -10.9098 -2.4022 -0.4118 1.8207 21.7340
##
## Coefficients:
## Estimate Std. Error t value Pr(>|t|)
## (Intercept) 13.0100 3.3193 3.919 9.83e-05 ***
## log(weight) 1.1396 0.7706 1.479 0.140
## countryCambodia 1.0189 0.8601 1.185 0.237
## countryColombia 1.1936 0.9866 1.210 0.227
## countryEthiopia 0.8401 0.7375 1.139 0.255
## countryIndia 0.4617 0.6165 0.749 0.454
## countryPeru 1.8961 0.3707 5.115 4.15e-07 ***
## countryPhilippines 3.0877 1.9975 1.546 0.123
## countryThailand -0.0647 0.4760 -0.136 0.892
## countryVietnam 0.4189 0.7178 0.584 0.560
## ---
## Signif. codes: 0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
##
## Residual standard error: 3.419 on 639 degrees of freedom
## (451 observations deleted due to missingness)
## Multiple R-squared: 0.06273, Adjusted R-squared: 0.04953
## F-statistic: 4.752 on 9 and 639 DF, p-value: 3.851e-06
##
## Pearson's product-moment correlation
##
## data: outcome_dat$weight and outcome_dat$t_12_terminal_rescaled
## t = 0.77929, df = 644, p-value = 0.4361
## alternative hypothesis: true correlation is not equal to 0
## 95 percent confidence interval:
## -0.04655608 0.10757919
## sample estimates:
## cor
## 0.03069403## Using all data (n=631), the odds ratio for recurrence at 4 months for each additional day in the tafenoquine half life is 1.1 (95% CI 1.04 to 1.17)## Using all data (n=631), the odds ratio for recurrence at 4 months for each additional day in the tafenoquine half life is 1.09 (95% CI 1.02 to 1.16)
## Using patients given 300 mg (n=467), the odds ratio for recurrence at 4 months for each additional day in the tafenoquine half life is 1.11 (95% CI 1.04 to 1.19)Methaemoglobin
## Using all TQ treated patients (n=569), the odds ratio for recurrence at 4 months for each absolute percentage increase in methaemoglobin is 0.82 (95% CI 0.67 to 0.99)## Under the TQ mg/kg dose EMAX model, each absolute percentage point increase in methaemglobin as associated in an odds-ratio for recurrence at 4 months of 0.81 (95% CI 0.66 to 0.98)Everything
## Generalized linear mixed model fit by maximum likelihood (Laplace
## Approximation) [glmerMod]
## Family: binomial ( logit )
## Formula:
## outcome_primary ~ tqmgkgtot + scale(log(day7_mthb)) + scale(t_12_terminal_rescaled) +
## scale(logpara0) + (1 | studysite)
## Data: outcome_dat
##
## AIC BIC logLik deviance df.resid
## 572.6 598.7 -280.3 560.6 560
##
## Scaled residuals:
## Min 1Q Median 3Q Max
## -1.2834 -0.5550 -0.3959 -0.1528 3.3272
##
## Random effects:
## Groups Name Variance Std.Dev.
## studysite (Intercept) 0.4004 0.6328
## Number of obs: 566, groups: studysite, 20
##
## Fixed effects:
## Estimate Std. Error z value Pr(>|z|)
## (Intercept) -0.10876 0.35907 -0.303 0.76197
## tqmgkgtot -0.29114 0.07571 -3.846 0.00012 ***
## scale(log(day7_mthb)) -0.24235 0.15054 -1.610 0.10741
## scale(t_12_terminal_rescaled) 0.25910 0.11259 2.301 0.02138 *
## scale(logpara0) 0.13395 0.11708 1.144 0.25257
## ---
## Signif. codes: 0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
##
## Correlation of Fixed Effects:
## (Intr) tqmgkg s((7_) s(_12_
## tqmgkgtot -0.800
## scl(lg(7_)) 0.346 -0.440
## scl(t_12__) 0.024 -0.073 0.159
## scal(lgpr0) 0.076 -0.079 0.023 0.101## Full model has 566 datapoints
CYP2D6
##
## FALSE TRUE
## 349 34##
## Brazil Cambodia Colombia Ethiopia India Peru Philippines Thailand
## FALSE 131 14 7 23 0 133 2 25
## TRUE 9 4 0 1 0 1 0 9
##
## Vietnam
## FALSE 14
## TRUE 10## Generalized linear mixed model fit by maximum likelihood (Laplace
## Approximation) [glmerMod]
## Family: binomial ( logit )
## Formula: outcome_primary ~ tqmgkgtot + as.numeric(AS_score <= 0.5) + (1 |
## studysite)
## Data: outcome_dat[ind_efficacy & outcome_dat$tqmgkgtot > 0, ]
##
## AIC BIC logLik deviance df.resid
## 417.2 433.0 -204.6 409.2 379
##
## Scaled residuals:
## Min 1Q Median 3Q Max
## -0.8107 -0.5730 -0.5045 -0.3959 2.7971
##
## Random effects:
## Groups Name Variance Std.Dev.
## studysite (Intercept) 0.01831 0.1353
## Number of obs: 383, groups: studysite, 15
##
## Fixed effects:
## Estimate Std. Error z value Pr(>|z|)
## (Intercept) 0.19208 0.62067 0.309 0.7570
## tqmgkgtot -0.29409 0.12717 -2.313 0.0207 *
## as.numeric(AS_score <= 0.5) -0.09062 0.45034 -0.201 0.8405
## ---
## Signif. codes: 0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
##
## Correlation of Fixed Effects:
## (Intr) tqmgkg
## tqmgkgtot -0.966
## a.(AS_<=0.5 -0.005 -0.064## OR for recurrence for poor versus normal/extensive CYP2D6 metabolisers is 0.9 [95% CI is 0.4 to 2.2]Phase 1: relationship with DHA/PQP?
##
## Call:
## glm(formula = log10(day7_mthb) ~ tqmgkgtot + TYPE, data = pk_summaries)
##
## Deviance Residuals:
## Min 1Q Median 3Q Max
## -1.1253 -0.1679 0.0104 0.1811 0.6181
##
## Coefficients:
## Estimate Std. Error t value Pr(>|t|)
## (Intercept) -0.151522 0.036502 -4.151 3.75e-05 ***
## tqmgkgtot 0.064592 0.004908 13.161 < 2e-16 ***
## TYPE 0.062112 0.033011 1.882 0.0603 .
## ---
## Signif. codes: 0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
##
## (Dispersion parameter for gaussian family taken to be 0.06901405)
##
## Null deviance: 57.344 on 649 degrees of freedom
## Residual deviance: 44.652 on 647 degrees of freedom
## (72 observations deleted due to missingness)
## AIC: 111.87
##
## Number of Fisher Scoring iterations: 2##
## CQ None AL DHA/PQP
## 578 24 24 24Power calculations and trial design
Power calculations
Superiority of 450 over 300 mg single dose